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      Clonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate

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          Abstract

          Ageing associates with significant alterations in somatic/adult stem cells and therapies to counteract these might have profound benefits for health. In the blood, haematopoietic stem cell (HSC) ageing is linked to several functional shortcomings. However, besides the recent realization that individual HSCs might be preset differentially already from young age, HSCs might also age asynchronously. Evaluating the prospects for HSC rejuvenation therefore ultimately requires approaching those HSCs that are functionally affected by age. Here we combine genetic barcoding of aged murine HSCs with the generation of induced pluripotent stem (iPS) cells. This allows us to specifically focus on aged HSCs presenting with a pronounced lineage skewing, a hallmark of HSC ageing. Functional and molecular evaluations reveal haematopoiesis from these iPS clones to be indistinguishable from that associating with young mice. Our data thereby provide direct support to the notion that several key functional attributes of HSC ageing can be reversed.

          Abstract

          Age-associated decline in tissue function has been linked to alterations in adult stem cells, with implications for organ homeostasis and cellular therapy. Here, the authors study the heterogeneity of ageing mouse haematopoietic stem cells (HSCs) and find that the compromised blood cell-forming potential of individual and functionally defined aged HSCs can be reset by reprogramming.

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          Most cited references18

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          Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion.

          Aging of the hematopoietic stem cell compartment is believed to contribute to the onset of a variety of age-dependent blood cell pathophysiologies. Mechanistic drivers of hematopoietic stem cell (HSC) aging include DNA damage accumulation and induction of tumor suppressor pathways that combine to reduce the regenerative capacity of aged HSCs. Such mechanisms do not however account for the change in lymphoid and myeloid lineage potential characteristic of HSC aging, which is believed to be central to the decline of immune competence and predisposition to myelogenous diseases in the elderly. Here we have prospectively isolated functionally distinct HSC clonal subtypes, based on cell surface phenotype, bearing intrinsically different capacities to differentiate toward lymphoid and myeloid effector cells mediated by quantitative differences in lineage priming. Finally, we present data supporting a model in which clonal expansion of a class of intrinsically myeloid-biased HSCs with robust self-renewal potential is a central component of hematopoietic aging.
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            Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy.

            The major myeloid blood cell lineages are generated from hematopoietic stem cells by differentiation through a series of increasingly committed progenitor cells. Precise characterization of intermediate progenitors is important for understanding fundamental differentiation processes and a variety of disease states, including leukemia. Here, we evaluated the functional in vitro and in vivo potentials of a range of prospectively isolated myeloid precursors with differential expression of CD150, Endoglin, and CD41. Our studies revealed a hierarchy of myeloerythroid progenitors with distinct lineage potentials. The global gene expression signatures of these subsets were consistent with their functional capacities, and hierarchical clustering analysis suggested likely lineage relationships. These studies provide valuable tools for understanding myeloid lineage commitment, including isolation of an early erythroid-restricted precursor, and add to existing models of hematopoietic differentiation by suggesting that progenitors of the innate and adaptive immune system can separate late, following the divergence of megakaryocytic/erythroid potential.
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              The ageing haematopoietic stem cell compartment.

              Stem cell ageing underlies the ageing of tissues, especially those with a high cellular turnover. There is growing evidence that the ageing of the immune system is initiated at the very top of the haematopoietic hierarchy and that the ageing of haematopoietic stem cells (HSCs) directly contributes to changes in the immune system, referred to as immunosenescence. In this Review, we summarize the phenotypes of ageing HSCs and discuss how the cell-intrinsic and cell-extrinsic mechanisms of HSC ageing might promote immunosenescence. Stem cell ageing has long been considered to be irreversible. However, recent findings indicate that several molecular pathways could be targeted to rejuvenate HSCs and thus to reverse some aspects of immunosenescence.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                22 February 2017
                2017
                : 8
                : 14533
                Affiliations
                [1 ]Lund University, Medical Faculty, Institution for Laboratory Medicine, Division of Molecular Hematology , Klinikgatan 26, BMC B12, 221 84 Lund, Sweden
                [2 ]Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California , Los Angeles, California 90033, USA
                [3 ]Biotech Research and Innovation Centre, Biomedical Institute, University of Copenhagen , 2200 Copenhagen, Denmark
                [4 ]Core Facility for Transgenic Mice, Department of Biomedical Sciences University of Copenhagen, The Panum Institute , 6.4, Blegdamsvej 3B, 2200 Copenhagen, Denmark
                [5 ]Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford University , Palo Alto, California 94305, USA
                [6 ]StemTherapy, Lund University
                Author notes
                Article
                ncomms14533
                10.1038/ncomms14533
                5322498
                28224997
                58a8befe-126e-4f4b-a7c7-111daa3b3ba0
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 08 August 2016
                : 06 January 2017
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